CASE REPORT Open Access

Aberrant growth of the anterior cranialbase relevant to severe midface hypoplasiaof Apert syndromeBong Kuen Cha1, Dong Soon Choi1, In San Jang1, Hyun Tae Yook2, Seung Youp Lee2, Sang Shin Lee3

and Suk Keun Lee3*

Abstract

Background: A 9-year-old male showed severe defects in midface structures, which resulted in maxillary hypoplasia,ocular hypertelorism, relative mandibular prognathism, and syndactyly. He had been diagnosed as having Apertsyndrome and received a surgery of frontal calvaria distraction osteotomy to treat the steep forehead at 6 months old,and a surgery of digital separation to treat severe syndactyly of both hands at 6 years old. Nevertheless, he still showeda turribrachycephalic cranial profile with proptosis, a horizontal groove above supraorbital ridge, and a short nose withbulbous tip.

Methods: Fundamental aberrant growth may be associated with the cranial base structure in radiological observation.

Results: The Apert syndrome patient had a shorter and thinner nasal septum in panthomogram, PA view, and Waters’view; shorter zygomatico-maxillary width (83.5 mm) in Waters’ view; shorter length between the sella and nasion(63.7 mm) on cephalogram; and bigger zygomatic axis angle of the cranial base (118.2°) in basal cranial view than anormal 9-year-old male (94.8 mm, 72.5 mm, 98.1°, respectively). On the other hand, the Apert syndrome patientshowed interdigitating calcification of coronal suture similar to that of a normal 30-year-old male in a skull PA view.

Conclusion: Taken together, the Apert syndrome patient, 9 years old, showed retarded growth of the anterior cranialbase affecting severe midface hypoplasia, which resulted in a hypoplastic nasal septum axis, retruded zygomatic axes,and retarded growth of the maxilla and palate even after frontal calvaria distraction osteotomy 8 years ago. Therefore,it was suggested that the severe midface hypoplasia and dysostotic facial profile of the present Apert syndromecase are closely relevant to the aberrant growth of the anterior cranial base supporting the whole oro-facial andforebrain development.

Keywords: Apert syndrome, Midface hypoplasia, Anterior cranial base, Retruded zygomatic axes

BackgroundApert syndrome is a rare autosomal dominant disordercharacterized by severe syndactyly of the feet and hands,craniofacial abnormalities, and craniosynostosis, which isalso known to be caused by one of the two specific pointmutations in the fibroblast growth factor receptor 2(FGFR2), i.e., Ser252Trp and Pro253Arg [1–3]. Therewas a trend of more frequent amblyopia and strabismusin FGFR2 Ser252Trp mutation and more frequent optic

disc pallor in the FGFR2 Pro253Arg mutation [4, 5].These differential effects of FGFR2 mutations in oph-thalmic findings in patients with Apert syndrome, withsignificantly greater prevalence of visual impairment inthe Ser252Trp mutation compared with that in thePro253Arg mutation, may imply a developmental eti-ology of mutated FGFR2 proteins which can functiondifferently [6]. The abnormal overexpression or accumu-lation of proteoglycan, i.e., decorin and biglycan, wasfound and presumed to be caused by the low affinity ofreceptor regulation in FGFR2 signaling cascade, whichresulted in premature periosteal ossification inducingmembranous bone dysostosis [7].

* Correspondence: sukkeunlee@hanmail.net3Department of Oral Pathology, College of Dentistry, Gangneung-WonjuNational University, 123 Chibyun-dong, Gangneung 210-702, South KoreaFull list of author information is available at the end of the article

Maxillofacial Plastic andReconstructive Surgery

© The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made.

Cha et al. Maxillofacial Plastic and Reconstructive Surgery (2018) 40:40 https://doi.org/10.1186/s40902-018-0179-8

When normal development and growth of the calvarialsutures is disrupted, craniosynostosis leading to an ab-normal head shape, ocular hypertelorism with proptosis,and midface hypoplasia may result. Classical craniosyn-ostosis syndromes are autosomal dominant traits andinclude Apert, Pfeiffer, Crouzon, Jackson-Weiss, andSaethre-Chotzen syndromes [8]. Apert syndrome is themost common among acrocephalosyndactylies withcomplex malformations of the hands. The Apert handrequires early and specialized treatment that aims toprovide a functional hand before 2 or 3 years, with theleast surgical complications. But the functional progno-sis is darkened by symphalangism [9, 10].The craniosynostosis of those with Apert syndrome is

usually associated with midface hypoplasia, exhibitingretruded maxilla, undergrowth of the nasal organ,septo-optic dysplasia, and other systemic malformations

including mental retardation [11]. Patients with Apertsyndrome frequently showed progressive widening of theskull base even after cranioplasty for bilateral coronalcraniosynostosis [12].Although the craniofacial dysostosis of those with

Apert syndrome may give great impact on the wholecraniofacial growth, the craniofacial structures of thosewith Apert syndrome have not been precisely analyzed sofar due to their complicated and heterogeneous develop-mental components. The present study tried to analyzethe radiological measurements of craniofacial structuresobtained from a 9-year-old Apert syndrome patient incomparison with those of an age-matched normal male.

Case reportThis case report has been approved by the InstitutionalReview Board (IRB2016–11). In order to explore his

Fig. 1 Photograph of an Apert syndrome patient, a 9-year-old male. Facial profile: frontal view (A1): hypertelorism, turribrachycephalic cranialprofile, horizontal groove above supra orbital ridge (arrows), and a short nose with bulbous tip. Lateral view (A2): retarded maxilla and frontalproptosis (arrows). Intraoral view: anterior view (B1): anterior open bite and poor oral hygiene. Lateral view (B2): retruded maxillary incisors. Upperocclusal view (C1): narrow and triangular shape maxillary arch with Byzantine arch-shaped palate. Lower occlusal view (C2): almost normalU-shaped mandibular arch with thick lingual frenum (arrows). D Plaster dental model: fissure-like palatal groove (arrows). E Hand, incompletelyseparated and with short fingers even after syndactyly operation performed 3 years ago

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Fig. 2 Panoramic view. a An Apert syndrome patient, a 9-year-old male, with an upward convex palatal plate (arrows) and a short and thin nasalseptum (arrow heads). Noted the severe anterior open bite (*). b A 9-year-old normal male with normal horizontal palatal plate (arrows) and along and thick nasal septum (arrow heads)

Fig. 3 Water’s view: An Apert syndrome patient (a), a 9-year-old male, showed a shorter zygomatico-maxillary width and a shorter and thinnernasal septum than a 9-year-old normal male (b)

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cranial base structures, the radiograms of panthomo-gram, posterior to anterior (PA) view, Waters’ view,cephalogram, and basal cranial view were taken andcompared with those of the control (age-matched nor-mal male subject). And the dental plaster model was alsomade to illustrate the precise situation of dental dimen-sions and palatal shape. Every radiological measurementperformed in the methods previously described was ana-lyzed for the significant abnormalities of Apert syndromecompared to the control [13].A 9-year-old male, diagnosed as Apert syndrome after

birth, was examined for his oro-facial abnormalities. Besidesthe severe syndactyly and cardiac anomaly of patent ductalarteriosus, he showed characteristic syndromic features ofcraniofacial synostosis, i.e., steep forehead, hypertelorism,turribrachycephalic cranial profile, horizontal groove abovesupra orbital ridge, and short nose with bulbous tip in an-terior facial profile, retruded maxilla and frontal proptosisin lateral facial profile, maxillary hypoplasia, and relativemandibular prognathism, (Fig. 1a). Intraoral observation

showed severe anterior open bite with poor oral hygiene.His maxillary incisors were severely retruded compared tomandibular incisors, which resulted in an anterior open bite(Fig. 1b). Upper dental arch was much narrow and formedtriangular shape palate similar to a Byzantine arch, whilemandibular arch was almost normal in U-shape attachedwith thick lingual frenum (Fig. 1c). Mid-palatal area wasdeeply grooved in a fissure-like fashion, but nasal perfor-ation was not found (Fig. 1d). His hand still showed shortfingers incompletely separated even after syndactyly oper-ation was performed 3 years ago (Fig. 1e).In panthomogram, the Apert syndrome patient

showed curved palatal plate which was upwardly convexand a relatively short and thin nasal septum, while thecontrol showed horizontal palatal plate and a long andthick nasal septum (Fig. 2).In Waters’ view, the length between the bilateral con-

densed buccal bony areas produced by the attachmentof maxillary process of zygomatic bone to the lateralprocess of the maxilla may represent the width of

Fig. 4 Cephalogram: a An Apert syndrome patient, a 9-year-old male, noted with retained suture wires for distraction osteotomy performed at6 months after birth. b A 9-year-old normal male. c overlapping cephalogram panels a and b by adjusting to the SN line. The Apert syndromepatient showed an increased posterior-anterior cranial base angle (angle PC-S-AC), a retruded maxilla, and a counter-clockwise growth of themandible compared to the control

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maxillary proper and has an implication for the growth ofthe maxilla; therefore, it was named zygomatico-maxillarywidth in this study. However, the zygomatico-maxillarywidth was much reduced in the Apert syndrome patient(83.5 mm) than in the control (94.8 mm) (Fig. 3).In the comparison of cephalograms between the Apert

syndrome patient and the control, the overlapped tra-cing images by adjusting the SN line disclosed that theApert syndrome patient showed decreased length be-tween the sella (S) to nasion (N) (63.7 mm), decreasedSNA angle (77.5°), and increased posterior-anterior cra-nial base angle (angle PC-S-AC, 151.7°) compared tothe control (72.5 mm, 85.5°, 135.2°, respectively). Themaxillary undergrowth and relative mandibular protru-sion was evident, resulting in the reverse angulation ofANB angle (− 3.3°) compared to the ANB angle (4°) ofthe control. Particularly, compared to the control, theApert syndrome patient had a smaller nasion, whichwas also hypoplastic and associated with small nasalseptal cartilage retruded markedly (Fig. 4).In the comparison of skull PA views between the

Apert syndrome patient and the control, the over-lapped tracing images by adjusting the line between

bilateral jugular points clearly disclosed that the Apertsyndrome patient showed severe orbital hypertelorismwith increased length between the centers of bilateralzygomatic bones, less descended nasal floor due tothe retarded growth of the nasal organ, and down-ward growth of the mandible compared to the control(Fig. 5).In basal cranial view, the Apert syndrome patient

showed much bigger zygomatic axis angle of the cranialbase (118.2°) and smaller otic axis angle of the cranial base(121.5°) than the control (98.1°, 131.8°, respectively), impli-cating that the zygomatic axes of the Apert syndrome pa-tient were retruded markedly compared to those of thecontrol, while the otic axes of the Apert syndrome patientwere rotated posteriorly compensatory to maintain themiddle cranial base volume compared to those of the con-trol (Fig. 6).In the skull PA view, the Apert syndrome patient

showed much more interdigitated and mineralized cor-onal suture than the control. The calvarial suture ossifi-cation of the present Apert syndrome patient wassimilar to that of a 30-year-old normal male selected asa representative one (Fig. 7).

Fig. 5 Posterior to anterior (PA) view. a An Apert syndrome patient, a 9-year-old male. b A 9-year-old normal male. c Overlapping panels a and bby adjusting the line between the bilateral jugular points. The Apert syndrome patient showed orbital hypertelorism, less descended nasal floor,and downward growth of the mandible compared to the control

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DiscussionAlthough the craniofacial structures are complicated andcomposed of heterogeneous components, their dynamicgrowth patterns could be well illustrated by different radio-logical methods. For the precise radiological observation ofcraniofacial structures, the panthomogram and skull PAview may show the vertical relationships of craniofacialstructures with the good images of nasal septal cartilage,and Water’s view may show the naso-maxillary structuresparallel to the anterior cranial base plane [14, 15]. Cephalo-gram may reveal the growth pattern of both jaws andposterior-anterior inclination of the cranial base on thesagittal plane [16]. And the basal cranial view may showthe whole cranial base structures composed of spheno-occipital synchondrosis, nasal septum axis, zygomaticaxes, and otic axes [17, 18]. However, to get the reliableradiological measurements, every radiogram for cranio-facial structures was taken in using the precise methodsby the trained expert.As the Apert syndrome is known as a craniosynostosis

originating from an abnormal FGFR2 protein which canproduce premature ossification of chondroid and osteoidtissues, the cranial base structures composed of active

osteochondroid tissue could be the primary target ofApert syndrome [1–3]. The abnormal growth patterns ofthe cranial base and midface structures, demonstrated inthis study, may be caused by premature osteosynchon-drosis of cranial base cartilages, i.e., spheno-occipitalcartilage and the associated axial cartilages, which arederived from the same prechordal mesoderm [19].Particularly, the zygomatic axis angle of the cranial

base was much bigger in the Apert syndrome patient,9-year-old male, than in the control. This fact may implythat in the Apert syndrome the zygomatic axes of the cra-nial base is premature and ossified before the appropriateanterior rotation of zygomatic axes as usual [19] so thatthe zygomatic axes of the Apert syndrome patient arehardly able to rotate anteriorly to support the anteriorcranial base structures. And subsequently, the anteriorcranial base became loosened and hypoplastic togetherwith the undergrowth of nasal organ cartilage [20, 21].Divergent types of craniofacial synostosis appeared with

the diagnosis of scaphocephaly, trigonocephaly, anteriorplagiocephaly, occipital plagiocephaly, and non-syndromicmulti-suture synostosis besides Crouzon syndrome andApert syndrome [22]. In Apert syndrome, including

Fig. 6 Basal cranial view. a An Apert syndrome patient, a 9-year-old male. b A 9-year-old normal male. c Overlapping panels a and b. The Apertsyndrome patient showed increased zygomatic axis angle of the cranial base (angle Z1-S-Z2) and decreased otic axis angle of the cranial base(angle O1-Oc-O2) compared to the control

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cranial deformities and syndactyly (acrocephalosyndac-tyly), although intracranial hypertension, exophthalmos,and midface hypoplasia were mild, the mandibular distrac-tion, in addition to fronto-orbital distraction, and Le FortIII midface distraction might give good results [23].The present case of Apert syndrome characteristically

exhibited the severe growth retardation of nasal organ car-tilage in the observation of all the radiograms, which re-sulted in the hypoplasia of nasal cavity structures includingthe nasal septum and nasal space. Subsequently, the aber-rant growth of the nasal organ may produce the hypoplas-tic premaxillo-septal ligament and vomer in the vicinity ofthe premaxilla and palate and negatively affect the expan-sile growth of the maxillary arch and palate. The presenceof fissure-like groove in the mid-palatal area was coinci-dent with the upward convex and high-positioned palatalplate in the panthomogram and less descended nasal floorin the skull PA view compared to the control. These find-ings may indicate that the growth of the whole nasal organincluding vomer is greatly retarded and became hypoplas-tic, consequently resulting in the severely retruded maxilla.

Actually, the forward growth of the maxilla cannot beachieved without the tensile force of premaxillo-septalligament attached between the premaxilla and nasalseptum, and the palatal bones have to anchor on thevomer located underneath the nasal septum to get thecounter force for the palatal expansion [24–26]. Thepresent Apert syndrome patient showed the severe hypo-plasia of the maxilla, accompanied with a less descendednasal floor in the skull PA view and fissure-like groove onthe mid-palate area in the intraoral observation.In Apert syndrome, there is a high incidence of raised

intracranial pressure, which can first occur at any age upto 5 years and may recur despite the initial successfultreatment of standard frontal-orbital advancement orfrontofacial monobloc advancement with pedicled flapsin multiple synostosis, trigonocephalies, and plagioce-phalies [27–29]. To ameliorate the brain development,the present Apert syndrome patient received a distrac-tion osteotomy of frontal calvaria at 6 months old, andnow at 9 years old, he showed a linear scar zone of newbone formation in the forehead by frontal calvaria ex-pansion. Fortunately, the present patient has no problemin the ear organ so far, but continuous follow-up checkshould be recommended for possible auditory defectsaddressed previously [30].The symptom complex caused by the raised intracra-

nial pressure in Apert syndrome could be a reliable hall-mark for the advance of craniosynostosis, which mayhave been continuously progressed from the develop-mental stage during the fetal period [31]. However, thefact that the Apert syndrome patient can feel the raisedintracranial pressure around 5 years of age may suggestthat any surgical or orthodontic treatment should bestarted at least from 5 years of age.On the other hand, in the present Apert syndrome pa-

tient, a 9-year-old male, the rhomboidal and coronal cal-varial suture in the skull PA view was tightly interdigitatedand almost calcified compared to the same-age male sub-ject. The suture maturation of the present 9-year-old pa-tient was similar to that of a 30-year-old male observed inthis study. Therefore, it was presumed that the craniofacialsynostosis was far advanced in the present Apert syn-drome patient, so that aberrant growth of the craniofacialstructure was supposed to be prematurely ossified to adegree.

ConclusionsWith the radiological observation of the craniofacialstructure of the Apert syndrome patient, it was foundthat the pathogenetic craniosynostosis of Apert syn-drome widely occurred not only in the midface struc-tures but also in the basic structures of the cranial base.Especially, the findings that the anterior rotation ofzygomatic axes of the cranial base was delayed and still

Fig. 7 Coronal sutures in PA X-ray views. a A 9-year-old normal malewith still immature coronal suture (arrows). b An Apert syndromepatient, a 9-year-old male, with tightly interdigitated coronal suture(arrows) similar to that of a 30-year-old normal male (c)

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insufficient and the fact that the nasal septum cartilagewhich functions as an anterior axis of the cranial basewas much undergrown may consequently affect the hy-poplastic growth of midface structures even after frontalcalvaria distraction osteotomy 8 years ago. As the cra-niofacial structures of Apert syndrome may producefundamental changes by premature osteosynchondrosisduring the early growth stage of postnatal period, it wasalso suggested that any surgical or orthodontic treat-ment should be carefully performed to adapt and tomodify the abnormal craniofacial structures as early aspossible at least from 5 years of age.

AcknowledgementsNot applicable.

FundingNot applicable.

Availability of data and materialsNot applicable.

Authors’ contributionsBKC conceived the study. BKC, DSC, ISJ, and SKL designed and coordinatedthe study. HTY collected the data. SYL and SSL undertook the statisticalanalysis. All authors helped to complete the manuscript and read andapproved the final manuscript.

Ethics approval and consent to participateThis case report has been approved by Institutional Review Board (IRB2016–11).

Consent for publicationThe authors received a consent for publication from his parents.

Competing interestsThe authors declare that they have no competing interests.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.

Author details1Department of Orthodontics, College of Dentistry, Gangneung-WonjuNational University, Gangneung, South Korea. 2Department of Orthodontics,College of Dentistry, Chunbuk National University, Jeonju, South Korea.3Department of Oral Pathology, College of Dentistry, Gangneung-WonjuNational University, 123 Chibyun-dong, Gangneung 210-702, South Korea.

Received: 10 October 2018 Accepted: 31 October 2018

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